ABSTRACT Reducing the incidence, severity, and complications of atherosclerotic cardiovascular (CV) disease in type 2 diabetes remains a key unmet medical need. Insulin resistance predisposes to atherosclerosis and worsens its macrovascular complications in patients with type 2 diabetes. While new anti-hyperglycemic drugs offer glimmers of hope to reduce the risk of CV events in diabetes, the relative disease burden remains large. Thus, treatments that address other aspects of diabetes pathogenesis, most notably insulin resistance, are needed. Interest in the effects of insulin sensitizers on atherosclerosis was rekindled by a recent study showing that the thiazolidinedione (TZD) insulin-sensitizer, pioglitazone, reduced the recurrence risk of cerebrovascular events in insulin-resistant patients with a recent ischemic stroke or transient ischemic attack. However, use of these agents is marred by serious adverse events, including worsening of congestive heart failure, fractures, and bladder cancer. In studies supported by this PPG, Drs. Accili and Qiang have shown that TZDs regulate the function of their target PPARg by deacetylating two amino acid residues, K268 and K293. They demonstrated that TZD-dependent deacetylation of PPARg modulates the latter?s ability to activate or repress target genes. In preliminary data, they show that mice homozygous for knock-in alleles of PPARg resulting in its constitutive deacetylation (K268R and K293R, thus 2KR) maintain the insulin-sensitizing response to rosiglitazone treatment, but don?t show reduced bone density, or increased fluid retention and heart rate. Further, in collaboration with Drs. Tabas and Tall, they show that atherosclerosis plaque formation is reduced in 2KR mice overexpressing PCSK9, and efferocytosis greatly increased in 2KR macrophages compared to WT. The PIs hypothesize that, when transferred on the Ldlr?/? background, the 2KR mutant PPARg will (a) decrease plaque formation, (b) reduce the adverse effects of TZD treatment on bone loss, cardiac hypertrophy, and fluid balance, and (c) promote atherosclerosis regression in animals with established lesions treated with TZD. To test the hypothesis, they will: in Aim 1 study the effect of the 2KR mutation on atherosclerosis progression and regression using crosses with Ldl receptor knockout mice (Ldlr?/?), followed by bone marrow transplants to determine the main site(s) of the expected protective effect. They will also examine whether 2KR-Ldlr?/? mice are protected from rosiglitazone?s adverse effects. In Aim 2 they will study the effect of 2KR in macrophage function, with a focus on efferocytosis (Tabas collaboration) and cholesterol efflux (Tall collaboration); in Aim 3 they will seek to identify the critical mediators of 2KR action by an integrative approach combining gene expression with genome-wide histone modification and enhancer studies in macrophages.